It is estimated that there will be more than 900,000 new cases of non- melanoma skin cancer (NMSC) diagnosed in the U.S. in 1997, accounting for approximately 40% of all cancer diagnoses. melanoma will account for 1-3% of new cancer cases (40,300 cases in 1997) but the incidence and mortality rates are increasing more rapidly than any other invasive cancer. Continued increases in NMSC are expected as the population ages and as larger amounts of UV radiation reach the earth's surface because of the depletion of the ozone layer. The overall goal of our Chemopreventative of Skin Cancer Program Project is to develop safe and highly efficacious intervention strategies for prevention of melanoma and non-melanoma skin cancers and to develop basic science and clinical research approaches which will serve as models for the chemoprevention of a wide range of human epithelial cancers. Our Program Project consists of four scientific research components designed by an outstanding group of dedicated skin carcinogenesis scientists to address our primary hypothesis-that chemopreventive agents can alter the natural history of skin cancer. . Preclinical studies of mechanisms of UV-induced carcinogenesis and mechanisms of action of topically applied chemoprevention agents in melanoma and NMSC animal models. . Clinical studies to establish the validity and reproducibility of histopathologic, morphometric, genetic, and immunohistochemical surrogate endpoint biomarkers, in participants with preclinical actinic keratoses, actinic keratoses, cutaneous squamous cell cancers, and dysplastic nevi. . Sequential phase IIa and IIb randomized double-blinded, placebo- controlled skin cancer prevention studies of chemoprevention agents selected because of their mechanistic effects on the skin carcinogenesis signal transduction pathway as well as documented activity in UVB skin carcinogenesis and transgenic melanoma animal models. . In depth evaluation of possible correlations between changes in histopathology/morphometry and alterations in genetic expressions (as evaluated by cDNA microarray and immunohistochemical assays in human epidermal tissue biopsies.